Narrative review of malignant ascites: epidemiology, pathophysiology, assessment, and treatment.

BACKGROUND AND OBJECTIVE: Malignant ascites (MA) is common in patients with advanced cancer, and about 60% of patients with MA experience distressing symptoms. In addition, MA has been identified as a poor prognostic factor, therefore, making the management of MA an important issue. We aimed to review literature describing MA provide a narrative synthesis of relevant studies. METHODS: A literature search of articles published between 1971 and May 2023 was performed in PubMed, and Cochrane library using the words "ascites/malignant ascites" and the theme of each section. Authors independently selected the articles used and summarized. Finally, this manuscript was obtained consensus through discussed among all authors. KEY CONTENT AND FINDINGS: The pathophysiological mechanism of ascites formation involves increased vascular permeability and impaired fluid drainage through the lymphatic system, which explain the occurrence of peritoneal carcinomatosis, portal hypertension due to liver tumors, liver cirrhosis in the background of hepatocellular carcinoma, and Budd-Chiari syndrome caused by tumor occlusion of the hepatic vein. The efficacy and safety of various treatments and procedures have been investigated previously; however, no treatment guidelines have been established yet. Diuretics and paracentesis are often selected as the first lines of treatment. Intraperitoneal drug administration (catumaxomab, bevacizumab, aflibercept, hyperthermic intraperitoneal chemotherapy, triamcinolone), indwelling peritoneal catheters, peritoneovenous shunting, and cell-free and concentrated ascites reinfusion therapy are commonly used to manage refractory ascites. A new device for this purpose is alfapump, which transfers ascites fluid from the peritoneum into the urinary bladder. In addition, thoracic epidural analgesia may be effective for managing ascites-related symptoms. CONCLUSIONS: Despite these options, no standard treatment for MA has been established yet because few trials have been conducted in this area. There are many issues to be investigated, and future research and treatment development are expected.

Impacts of fluid retention on prognostic abilities of cachexia diagnostic criteria in cancer patients with refractory cachexia.

BACKGROUND & AIMS: The international cancer cachexia criteria with a cutoff of 5% weight loss (WL) was proposed in Western patients. The Asian Working Group for Cachexia (AWGC) developed new criteria in Asian patients. The AWGC criteria are not cancer-specific and employ a cutoff of 2% WL. However, it is unclear whether both criteria are useful in patients with very advanced cancer because WL can be underestimated owing to fluid retention. Therefore, this study aimed to investigate the impacts of fluid retention on the prognostic abilities of both criteria in cancer patients with weeks of survival. METHODS: This study involved a secondary analysis of a prospective cohort study. The inclusion criteria constrained the study to adult patients with advanced cancer. Patients were divided into Non-cachexia and Cachexia groups using the international criteria and AWGC criteria. We performed time-to-event analyses using the Kaplan-Meier method and log-rank tests, and by conducting univariate and multivariate Cox regression analyses. RESULTS: A total of 402 patients were included in the analysis. Using the international criteria, the p-values for the log-rank test and stratified log-rank test for the mixed patients with and without fluid retention were 0.55 and 0.18, respectively. Using the AWGC criteria, the p-values for the log-rank test and stratified log-rank test for the mixed patients with and without fluid retention were 0.38 and 0.12, respectively. Without considering the impacts of fluid retention, no significant differences were observed between the Non-cachexia and Cachexia groups for both criteria. After adjusting for the status of fluid retention, significantly higher risks of mortality were not observed in the Cox proportional hazard model for the Cachexia group compared with the Non-cachexia group, for both criteria. However, significant associations were observed between fluid retention and overall survival. CONCLUSIONS: The international criteria and AWGC criteria lost their prognostic abilities in cancer patients with weeks of survival. Since measurements of %WL were significantly confounded by fluid retention, fluid retention-adjusted criteria for cachexia need to be developed for cancer patients with refractory cachexia.

Successful Management of Terminal Delirium With Transdermal Blonanserin Patch in a Terminally Ill Cancer Patient.

Delirium is a distressing condition in terminally ill cancer patients, often treated with antipsychotics. Administering them orally, subcutaneously, or intravenously can be challenging in severely agitated patients. Transdermal antipsychotic patches offer an alternative, but their use for terminal delirium remains underexplored. We present the case of a 73-year-old man with advanced diffuse large B cell lymphoma who developed severe mixed delirium during third-line chemotherapy. Nonpharmacological interventions and oral risperidone plus intravenous haloperidol failed to improve his condition. Subsequently, a transdermal blonanserin patch was applied, resulting in the resolution of hallucinations on day 1 and agitation on day 3, allowing improved communication. The patch was easily applied daily without notable adverse events. However, he deteriorated a week later with an estimated survival of days, ultimately requiring continuous midazolam for refractory agitation. This case underscores the potential of transdermal blonanserin patches for delirium in terminally ill cancer patients, emphasizing the need for future prospective studies.

Comparison of Pharmacological Treatments for Agitated Delirium in the Last Days of Life.

CONTEXT: Antipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited. OBJECTIVES: To explore the comparative effectiveness of haloperidol with as-needed benzodiazepines (HPD) vs. chlorpromazine (CPZ) vs. levomepromazine (LPZ) for agitated delirium in the last days. METHODS: A prospective observational study was conducted in two palliative care units in Japan. Adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS-PAL) of one or more were included; palliative care specialist physicians determined that the etiology was irreversible; and estimated survival was 3 weeks or less. Patients treated with HPD, CPZ, or LPZ were analyzed. We measured RASS, NuDESC, Agitation Distress Scale (ADS), and Communication Capacity Scale (CCS) on Days 1 and 3. RESULTS: A total of 277 patients were enrolled, and 214 were analyzed (112 in HPD, 50 in CPZ, and 52 in LPZ). In all groups, the mean RASS-PAL score significantly decreased on Day 3 (1.37 to -1.01, 1.87 to -1.04, 1.79 to -0.62, respectively; P < 0.001); the NuDESC and ADS scores also significantly decreased. The percentages of patients with moderate to severe agitation and those with full communication capacity on Day 3 were not significantly different. The treatments were well-tolerated. While one-fourth of HPD group changed antipsychotics, 88% or more of CPZ and LPZ groups continued the initial antipsychotics. CONCLUSION: Haloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation. Chlorpromazine and levomepromazine may have an advantage of no need to change medications.

Fluid retention and weight loss in refractory cancer cachexia.

OBJECTIVES: It is unknown to what extent the fluid retention (FR) status disrupts the detection of weight loss rate (WLR) in adult patients with advanced cancer. This study aimed to determine the association of FR status with WLR. METHODS: This study was a secondary analysis of a prospective cohort study. FR was evaluated as follows: oedema (0, no; 1, yes), pleural effusion (0, no; 1, yes but asymptomatic; 2, symptomatic) and ascites (0, no; 1, yes but asymptomatic; 2, symptomatic). Patients were divided into three groups according to their FR scores: no-FR (0), moderate-FR (1-2) and high-FR (3-5). Multiple regression analysis was performed. RESULTS: Four hundred and twenty patients were categorised: no-FR group (n=164), moderate-FR group (n=158) and high-FR group (n=98). The prevalence of oedema, pleural effusion and ascites was 63.9%, 27.8% and 36.7% in the moderate-FR group, and 93.9%, 61.3% and 82.6% in high-FR group. The means of WLR were 9.2, 8.4 and 3.8 in the groups. The high-FR group and the FR score of 5 were correlated with WLR (estimate -4.71, 95% CI -7.84 to -1.58; estimate -10.29, 95% CI -17.84 to -2.74). CONCLUSIONS: The coexistence of FR was significantly correlated with WLR.

Malignancy-related ascites in palliative care units: prognostic factor analysis.

OBJECTIVES: The prognostic factors in patients with malignancy-related ascites (MA) have been poorly investigated. This study aimed to evaluate both the prognostic impact of MA on terminally ill patients with cancer and the prognostic factors in those with MA. METHODS: This was a post hoc analysis of a multicentre, prospective cohort study. Patients with advanced cancer admitted to palliative care units at 23 institutions and aged≥18 years were enrolled between January and December 2017. Overall survival (OS) was compared according to MA. A multivariate analysis was conducted to explore prognostic factors in patients with MA. RESULTS: Of 1896 eligible patients, gastrointestinal and hepatobiliary pancreatic cancers accounted for 42.5%. 568 (30.0%) of the total had MA. Patients with MA had significantly shorter OS than those without MA (median, 14 vs 22 days, respectively; HR, 1.55; 95% CI, 1.39 to 1.72; p<0.01). A multivariate analysis showed that MA was a poor prognostic factor (HR, 1.30; 95% CI, 1.13 to 1.50; p<0.01) and that among patients with MA, significant poor prognostic factors were liver metastasis, moderately to severely reduced oral intake, delirium, oedema, gastric cancer, high serum creatinine, high serum C reactive protein, high serum total bilirubin, dyspnoea and fatigue, while significant good prognostic factors were female sex, good performance status, high serum albumin and colorectal cancer. CONCLUSIONS: MA had a negative impact on survival in terminally ill patients with cancer. A multivariate analysis revealed several prognostic factors in patients with terminal cancer and MA.

Psychological symptom burden associated with malignant wounds: Secondary analysis of a prospective cohort study.

OBJECTIVES: Patients with malignant wounds suffer from physical and psychological symptom burden. Despite psychological support being required, the impact of malignant wounds on patients' psychological distress is poorly investigated. We evaluated psychological distress associated with malignant wounds for patients at their end of life. METHODS: This study used the secondary analysis of the results of a large prospective cohort study, which investigated the dying process among patients with advanced cancer in 23 palliative care units in Japan. The primary outcome of this study was the prevalence of moderate to severe psychological symptom burden, evaluated by the Integrated Palliative Care Outcome Scale (IPOS)-feeling at peace scores of 2-4. In addition, the factors affecting psychological symptoms were investigated. The quality of death was also evaluated upon death using the Good Death Scale score. RESULTS: Out of the total 1896 patients, 156 had malignant wounds (8.2%). Malignant wounds were more common in female and young people. The breast, head, and neck were the most prevalent primary sites. More patients with malignant wounds had IPOS-feeling at peace scores of 2-4 than patients without malignant wounds (41.0% vs. 31.3%, p = 0.024). Furthermore, psychological distress was associated with moderate to severe IPOS-pain and the frequency of dressing changes. The presence of malignant wounds did not affect the quality of death. SIGNIFICANCE OF RESULTS: This study showed increased psychological distress due to malignant wounds. Patients with malignant wounds require psychological support in addition to the treatment of physical symptoms for maintaining their quality of life.

Prevalence of opioid-induced adverse events across opioids commonly used for analgesic treatment in Japan: a multicenter prospective longitudinal study.

PURPOSE: Although opioids have been shown to be effective for cancer pain, opioid-induced adverse events (AEs) are common. To date, little is known about the differences in risks of AEs by opioid type. This study was performed to compare the prevalence of AEs across opioids commonly used for analgesic treatment in Japan. METHODS: This study was conducted as a preplanned secondary analysis of a multicenter prospective longitudinal study of inpatients with cancer pain who received specialized palliative care for cancer pain relief. We assessed daily AEs until termination of follow-up. We rated the severity of AEs based on the Common Terminology Criteria for Adverse Events version 5.0. We computed adjusted odds ratios for each AE (constipation, nausea and vomiting, delirium, and drowsiness) with the following variables: opioid, age, sex, renal dysfunction, and primary cancer site. RESULTS: In total, 465 patients were analyzed. Based on the descriptive analysis, the top four most commonly used opioids were included in the analysis: oxycodone, hydromorphone, fentanyl, and tramadol. With respect to the prevalence of AEs among all analyzed patients, delirium (n = 25, 6.3%) was the most frequent, followed by drowsiness (n = 21, 5.3%), nausea and vomiting (n = 19, 4.8%), and constipation (n = 28, 4.6%). The multivariate logistic analysis showed that no single opioid was identified as a statistically significant independent predictor of any AE. CONCLUSION: There was no significant difference in the prevalence of AEs among oxycodone, fentanyl, hydromorphone, and tramadol, which are commonly used for analgesic treatment in Japan.

Continuous Deep Sedation for Psycho-Existential Suffering: A Multicenter Nationwide Study.

Background: There is ongoing debate on whether continuous deep sedation (CDS) for psycho-existential suffering is appropriate. Objective: We aimed to (1) clarify clinical practice of CDS for psycho-existential suffering and (2) assess its impact on patients' survival. Methods: Advanced cancer patients admitted to 23 palliative care units in 2017 were consecutively enrolled. We compared patients' characteristics, CDS practices, and survival between those receiving CDS for psycho-existential suffering ± physical symptoms and only for physical symptoms. Results: Of 164 patients analyzed, 14 (8.5%) received CDS for psycho-existential suffering ± physical symptoms and only one of them (0.6%) solely for psycho-existential suffering. Patients receiving CDS for psycho-existential suffering, compared with those only for physical symptoms, were likely to have no specific religion (p = 0.025), and desired (78.6% vs. 22.0%, respectively; p < 0.001) and requested a hastened death more frequently (57.1% vs. 10.0%, respectively; p < 0.001). All of them had a poor physical condition with limited estimated survival, and mostly (71%) received intermittent sedation before CDS. CDS for psycho-existential suffering caused greater physicians' discomfort (p = 0.037), and lasted for longer (p = 0.029). Dependency, loss of autonomy, and hopelessness were common reasons for psycho-existential suffering that required CDS. The survival time after CDS initiation was longer in patients receiving it for psycho-existential suffering (log-rank, p = 0.021). Conclusion: CDS was applied to patients who suffered from psycho-existential suffering, which often associated with desire or request for a hastened death. Further studies and debate are warranted to develop feasible treatment strategies for psycho-existential suffering.

Comparison of Symptom Severity and Progression in Advanced Cancer Patients Among Different Care Settings: A Secondary Analysis.

Background: Most people in Japan wish to spend their final days at home, but the majority fail to do so; earlier studies indicated a more pronounced worsening of symptoms if treated at home. Objectives: This study compared the prevalence of symptom worsening and explored associated factors between patients with advanced cancer receiving palliative care in palliative care units (PCUs) and at home. Design: We conducted a secondary analysis of two multicenter, prospective cohort studies involving patients with advanced cancer receiving palliative care in PCUs or at home. Setting/Subjects: One study was conducted at 23 PCUs (January to December 2017) and the other on 45 palliative home care services (July to December 2017) in Japan. Measurements: Symptom changes were categorized as stable, improved, or worse. Results: Of the 2998 registered patients, 2877 were analyzed. Among them, 1890 patients received palliative care in PCUs, and 987 at home. Patients receiving palliative care at home were more likely to have worsening of pain (17.1% vs. 3.8%; p < 0.001) and drowsiness (32.6% vs. 22.2%; p < 0.001) than those in PCUs. By multivariate logistic regression analysis, palliative care at home was significantly associated with worsening of the Palliative Prognostic Index dyspnea subscale in the unadjusted model (odds ratio, 1.42 [95% confidence interval, 1.08-1.88]; p = 0.014) but not for any symptoms in the adjusted model. Conclusions: After adjusting for patient background, the prevalence of symptom worsening was not different between patients with advanced cancer receiving palliative care at home and in PCUs.

Cross-cultural comparison of continuous deep sedation for advanced cancer patients in East Asian countries: prospective cohort study.

OBJECTIVE: Cultural, social, and legal factors have been known to affect physicians' practice of continuous deep sedation. There have been few quantitative studies to compare continuous deep sedation practice in Asian countries. We aimed to describe and compare clinical characteristics of continuous deep sedation in Japan, Korea and Taiwan. METHODS: Patients with advanced cancer admitted to participating palliative care units were enrolled from January 2017 to September 2018. We evaluated and compared (i) the prevalence of continuous deep sedation, (ii) the characteristics of sedated and non-sedated groups in each country, and (iii) continuous deep sedation administration patterns among the three countries. RESULTS: A total of 2158 participants were included in our analysis, and 264 received continuous deep sedation. The continuous deep sedation prevalence was 10, 16 and 22% in Japan, Korea and Taiwan, respectively. Delirium was the most frequent target symptom in all countries, along with dyspnoea (in Japan) and psychological symptoms (in Korea). Midazolam was most frequently used in Japan and Taiwan, but not in Korea (P < 0.001). Among the patients receiving continuous deep sedation, the hydration amount on the final day was significantly different, with median volumes of 200, 500 and 0 mL in Japan, Korea and Taiwan, respectively (P < 0.001). In Korea, 33% of the continuous deep sedation administration caused a high degree of physicians' discomfort, but 3% in Japan and 5% in Taiwan (P < 0.001). CONCLUSIONS: Clinical practices of continuous deep sedation and physicians' discomfort related to continuous deep sedation initiation highly varied across countries. We need to develop optimal decision-making models of continuous deep sedation and hydration during continuous deep sedation in each country.

Do Types of Opioids Matter for Terminal Cancer Dyspnea? A Preliminary Multicenter Cohort Study.

CONTEXT: Dyspnea is among the most distressing symptoms in the last weeks to days of life (terminal dyspnea). While physicians frequently use parenteral opioids other than morphine for terminal dyspnea, little is known about their effects in cancer patients. OBJECTIVES: To explore the effectiveness and safety of parenteral morphine, oxycodone, and hydromorphone for cancer patients with terminal dyspnea. METHODS: This was a secondary analysis of a multicenter cohort study that consecutively enrolled advanced cancer patients with moderate/severe terminal dyspnea. Participating palliative care physicians initiated parenteral opioids (morphine/oxycodone/hydromorphone), utilizing a standardized treatment algorithm. We examined the dyspnea intensity (Integrated Palliative care Outcome Scale [IPOS]) at 24 and 48 hours. RESULTS: Of 108 patients (mean age = 72), 66 (61%), 34 (32%), and 8 (7.4%) received morphine, oxycodone, and hydromorphone, respectively. At 24 hours, mean dyspnea IPOS scores significantly decreased from 3.0 (standard error (SE) = 0.1) at the baseline to 1.6 (0.1), 2.9 (0.1) to 2.0 (0.2), and 3.5 (0.2) to 1.2 (0.4) in the morphine (P < 0.001), oxycodone (P < 0.001), and hydromorphone (P = 0.011) groups, respectively. At 48 hours, the IPOS scores significantly reduced from 2.9 (0.1) at the baseline to 1.4 (0.1), 2.9 (0.1) to 1.6 (0.2), and 3.5 (0.2) to 1.2 (0.2) in the morphine (P < 0.001), oxycodone (P < 0.001), and hydromorphone (P = 0.004) groups, respectively. No significant differences in mean scores were found among the three groups at 24 (P = 0.080) and 48 hours (P = 0.322). Adverse events were rare. CONCLUSION: Parenteral morphine, oxycodone, and hydromorphone may be similarly effective and safe for cancer patients with terminal dyspnea.

Comparison of survival times of advanced cancer patients with palliative care at home and in hospital.

OBJECTIVES: One primary concern about receiving care at home is that survival might be shortened because the quality and quantity of treatment provided at home will be inferior to that given in the hospital. Although our previous study demonstrated a longer survival of those with home-based palliative care (PC), it lacked adjustment for some potential confounders including symptoms and treatments during the stay. We aimed to compare the survival times among advanced cancer patients receiving home-based and hospital-based PC with adjusting for symptoms and treatments. METHOD: We compared survival time of participants who enrolled two multicenter, prospective cohort studies of advanced cancer patients at 45-home-based PC services between July 2017 and December 2017, and at 23-hospital-based PC services between January 2017 and December 2017. We analyzed with stratification by the estimated survival of Days, Weeks, and Months, which were defined by modified Prognosis in Palliative care Study predictor models-A. We conducted a Cox regression analysis with adjusting for potential confounders including symptoms and treatments during the stay. RESULTS: A total of 2,998 patients were enrolled in both studies and 2,878 patients were analyzed; 988 patients receiving home-based PC and 1,890 receiving hospital-based PC. The survival time of patients receiving home-based PC was significantly longer than that of patients receiving hospital-based PC for the Days Prognosis (estimated median survival time: 10 days [95% CI 8.1-11.8] vs. 9 days [95% CI 8.3-10.4], p = 0.157), the Weeks prognosis (32 days [95% CI 28.9-35.4] vs. 22 days [95% CI 20.3-22.9], p < 0.001), and the Months Prognosis, (65 days [95% CI 58.2-73.2] vs. 32 days [95% CI 28.9-35.4], p < 0.001). CONCLUSION: In this cohort of advanced cancer patients with a Weeks or Months prognosis, those receiving home-based PC survived longer than those receiving hospital-based PC after adjusting for symptoms and treatments.

Visualizing How to Use Antipsychotics for Agitated Delirium in the Last Days of Life.

CONTEXT: How physicians use antipsychotics for agitated delirium in the last days of life varies markedly, which could hamper the quality of care. OBJECTIVES: To examine adherence to an algorithm-based treatment for terminal agitated delirium, and explore its effectiveness and safety. METHODS: A single-center, prospective, observational study was conducted in a 27-bed palliative care unit in Japan. All adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS) of +1 or more were included; the palliative care specialists determined that the etiology was irreversible, the estimated survival was three weeks or less, and the Eastern Cooperative Oncology Group (ECOG) performance status was three or four. Patients were treated with an algorithm to visualize how to use antipsychotics, with the treatment goal defined as no agitation (RASS≤0) or acceptable agitation for patients and families. We provided all patients nonpharmacological management to alleviate the symptoms of delirium and administered antipsychotic medications when the nonpharmacological approach was insufficient. We measured the adherence rate, RASS, Nursing Delirium Screening Scale items 2, 3, 4 (Nu-DESC), and Agitation Distress Scale item 2 (ADS) on days 0, 1, 3, 7, 14, 21, and 24 hours before death. RESULTS: A total of 164 patients were enrolled. Adherence rates were 99, 94, and 89%, and treatment goals were achieved in 66, 83, and 93% on days one, three, and seven, respectively. The mean RASS decreased from +1.41 to -0.84 on day three; Nu-DESC decreased from 4.19 to 1.83, and ADS decreased from 1.54 to 0.38. There were seven severe adverse events (Common Terminology Criteria for Adverse Events (CTCAE) of 3), including aspiration (n = 3), apnea (n = 2), tremor (n = 1), and muscle rigidity (n = 1) on day three. CONCLUSION: The algorithm-based treatment could be feasible, effective, and safe. Visualizing how palliative care specialists provide pharmacological management could be beneficial for nonspecialist clinicians, and clinical, educational, and research implications warrant further empirical testing.

Impact of taste/smell disturbances on dietary intakes and cachexia-related quality of life in patients with advanced cancer.

PURPOSE: Taste and smell are used to enjoy meals; however, impairments of these sensory perceptions seriously impact health and eating habits. This study is aimed at investigating the impact of taste and smell disturbances on dietary intakes and cachexia-related quality of life (QOL) in patients with advanced cancer. METHODS: Using a self-report questionnaire, we surveyed patients with advanced cancer undergoing treatment at 11 palliative care centers. Multivariate analyses were conducted to explore the impact of taste and smell disturbances on dietary intakes and cachexia-related QOL. Dietary intakes were assessed using the Ingesta-Verbal/Visual Analog Scale, while taste and smell disturbances were assessed using an 11-point Numeric Rating Scale (NRS). Cachexia-related QOL was assessed using the Functional Assessment of Anorexia/Cachexia Therapy Anorexia Cachexia Subscale (FAACT ACS). RESULTS: Overall, 378 patients provided consent to participate. After excluding patients with missing data, data were analyzed for 343 patients. Among them, 35.6% (n = 122; 95% [confidence interval (CI)] 0.28-0.38) and 20.9% (n = 72; 95% CI 0.17-0.25) experienced disturbances in taste (NRS ≥ 1) and smell (NRS ≥ 1), respectively. Multivariate analyses revealed that, independent of performance status and cancer cachexia, taste and smell disturbances were significantly associated with worse dietary intakes and deteriorating FAACT ACS scores. CONCLUSION: More severe taste and smell disturbances were associated with poorer dietary intakes and cachexia-related QOL. Diagnosing and treating such disturbances may improve dietary intakes and cachexia-related QOL, regardless of performance status and cachexia.

The feasibility and effects of a pharmacological treatment algorithm for cancer patients with terminal dyspnea: A multicenter cohort study.

BACKGROUND: How clinicians treat patients with terminal dyspnea widely varies, which could hamper quality care. We visualized comprehensive pharmacological treatment delivered by palliative care physicians. AIM: To examine adherence to a comprehensive pharmacological treatment algorithm for patients with terminal dyspnea, and to explore its outcomes during 48 h. DESIGN: A multicenter cohort study at five sites (February 2020 to June 2021). SETTING/PARTICIPANTS: We prospectively enrolled consecutive patients with advanced cancer, Eastern Cooperative Oncology Group performance status 3-4, and moderate/severe dyspnea. Participating palliative care physicians initiated algorithm-based treatment. The primary outcome was the proportion of adherence to the treatment algorithm over 24 h (predefined goal, 70%). We evaluated the adherence, goal achievement, and dyspnea level with a numerical rating scale (NRS), as well as adverse events over 48 h. RESULTS: All 108 patients received algorithm-based pharmacological treatment. Among 96 and 87 patients who were alive at 24 and 48 h, respectively, 96 (100%; 95% confidence interval [CI] = 96%-100%) and 82 (94%; 95%CI = 87%-98%) continued to receive the algorithm treatment, respectively, and 66 (69%; 95%CI = 59%-77%) and 64 (74%; 95%CI = 63%-82%) achieved the treatment goals, respectively. Using a complete case analysis with paired t-tests, mean dyspnea NRS scores significantly reduced from 7.3 (standard error, 0.2) at the baseline to 4.9 (0.3) at 24 h (n = 72; p < 0.001), and 7.2 (0.3) at the baseline to 4.6 (0.4) at 48 h (n = 55; p < 0.001). Most adverse events were mild to moderate. CONCLUSIONS: The comprehensive pharmacological treatment algorithm was feasible, and the study data supports its preliminary efficacy and safety. The use of this algorithm may help clinicians improve care for patients with terminal dyspnea.

Anticholinergic drugs for death rattle in dying patients with cancer: multicentre prospective cohort study.

BACKGROUND: This study aimed to investigate the effectiveness of anticholinergics (AC) for death rattle in dying patients with cancer. METHODS: This is a prospective cohort study enrolled Terminally ill adult (20 years or older) patients with cancer who developed substantial death rattle (Back score ≥2) from 23 palliative care units in Japan. AC treatment for death rattle was prescribed according to primary physician's decision. The primary outcome was the proportion of patients whose death rattle improved, which was defined as a Back score of ≤1. We compared the proportion of improved cases in patients treated with (AC group) and without (non-AC group) AC, controlling potential confounders by employing propensity score weighting. RESULTS: Of the 1896 patients enrolled, we included 196 who developed a substantial death rattle. Of these, 81 received AC. 56.8% in the AC group and 35.4% in the non-AC group had an improved death rattle at 8 hours after baseline. In the weighted analysis, AC group showed significant improvements in death rattle, with an adjusted OR of 4.47 (95% CI 2.04 to 9.78; p=0.0024). All sensitivity analyses achieved essentially the same results. In the subgroup analysis, ACs were strongly associated with death rattle improvement in men, patients with lung cancer, and type 1 death rattle (adjusted OR 5.81, 8.38 and 9.32, respectively). CONCLUSIONS: In this propensity score-weighted analysis, ACs were associated with death rattle improvement in terminally ill patients with cancer who developed substantial death rattle. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN00002545).

Association of the RASS Score with Intensity of Symptoms, Discomfort, and Communication Capacity in Terminally Ill Cancer Patients Receiving Palliative Sedation: Is RASS an Appropriate Outcome Measure?

Background: Palliative sedation is sometimes needed for refractory symptoms, and the Richmond Agitation-Sedation Scale (RASS) is one of the key measures. The primary aim of this study was to explore the association between RASS and degree of distress quantified by other measures: Item "symptom control" of Support Team Assessment Schedule (STAS, item 2), Discomfort Scale for Dementia of Alzheimer Type (Discomfort Scale), and Noncommunicative Patient's Pain Assessment Instrument (NOPPAIN), as well as a communication capacity measured by the Communication Capacity Scale (CCS), item 4. Methods: This was a prospective observational study on terminally ill cancer patients with palliative sedation in a palliative care unit of a designated cancer hospital. Primarily responsible palliative care physicians rated RASS, Discomfort Scale, NOPPAIN, and CCS just before sedation and 1, 4, 24, and 48 hours after, and ward nurses rated STAS at the same time. Since the ward nurses evaluated STAS during palliative sedation, we regarded STAS as a standard of distress measure. Results: A total of 249 assessments were performed for 55 patients. RASS was moderately to highly associated with symptom intensity measured by STAS, discomfort measured by the Discomfort Scale, and pain measured by NOPPAIN (r = 0.63 to 0.73). But communication capacity measured by CCS is not parallel with RASS and demonstrated a valley shape. In 82 assessments with an RASS score of -1 to -3, 11 patients (13%) had physical symptoms of STAS of 2 or more. Conclusions: RASS can roughly estimate physical distress in patients with palliative sedation, but a measure to more precisely quantify the symptom experience is needed.

Effect of paracentesis on the survival of patients with terminal cancer and ascites: a propensity score-weighted analysis of the East Asian Collaborative Cross-cultural Study to Elucidate the Dying Process.

PURPOSE: Paracentesis is among the most widely utilized treatments for malignant ascites (MA). However, paracentesis in patients with MA has the potential to be associated with life-shortening effects. Thus, this study aimed to investigate whether paracentesis affected the duration of survival in such patients. METHODS: We performed a post hoc analysis of a prospective multicenter observational study investigating the dying process and end-of-life care in patients with terminal cancer, admitted to 23 palliative care units in Japan. Survival duration was compared between patients who did (paracentesis group) and did not undergo paracentesis (non-paracentesis group). We used inverse probability of treatment weighting (IPTW) to control for baseline covariates between groups. RESULTS: Among the 1896 initially enrolled patients, 568 with ascites were included in the study cohort. Eighty-five (15.0%) patients underwent paracentesis. The primary tumor site was the pancreas (51.9%, n = 295), followed by the gastrointestinal tract (22.7%, n = 129). Non-adjusted median durations of survival were 22 days (95% confidence interval [CI]: 16-25) and 12 days (95% CI: 11-13) in the paracentesis and non-paracentesis groups, respectively (hazard ratio [HR]: 0.69, 95% CI: 0.54-0.88; p = 0.003). The IPTW-adjusted median survival durations were 22 (95% CI: 16-25) and 16 days (95% CI: 12-22) in the paracentesis and non-paracentesis groups, respectively (HR: 0.89, 95% CI: 0.64-1.24; p = 0.492). No serious adverse events occurred in the paracentesis group. CONCLUSIONS: Paracentesis does not negatively affect the survival of patients with cancer and MA and can be a standard treatment in palliative care settings.

Association of Antipsychotic Dose With Survival of Advanced Cancer Patients With Delirium.

CONTEXT: Delirium is common in patients with advanced cancer, and antipsychotics are widely used for its management. OBJECTIVES: We aimed to explore the association of the antipsychotic dose with survival of terminally ill cancer patients with delirium. METHODS: A secondary analysis of a multicenter prospective observational study was conducted. We enrolled adult advanced cancer patients who developed delirium and received antipsychotics at 14 palliative care units in Japan between September 2015 and May 2016. Hazard ratios of survival after starting antipsychotics between groups with different oral chlorpromazine equivalent doses: low: <100 mg, moderate: 100-200 mg, high: ≥200 mg, were calculated with adjustment for potential confounders using Cox regression. The antipsychotic dose-specific mortality risk was estimated with smooth splines. RESULTS: Of 453 patients enrolled, 422 patients were analyzed. The median antipsychotic dose was 92.6 mg: low-dose (N = 231), moderate-dose (122), and high-dose (69). The median survival of all patients was 11 days. Compared with the low-dose group, the high-dose group showed a significantly shorter survival (HR: 1.46, 95%CI: 1.08-1.98). Smooth splines demonstrated that HR continuously increased as the antipsychotic dose increased. In patients treated with atypical antipsychotics, the high-dose group showed a significantly shorter survival than the low-dose group (HR: 2.86), while in patients treated with typical antipsychotics, survival was not significantly different (0.99). CONCLUSIONS: Higher doses of antipsychotics were associated with increased mortality in terminally ill cancer patients with delirium. To minimize the potential mortality risk, antipsychotics should be started at low doses and titrated carefully.